SeSAME/EAST syndrome-phenotypic variability and delayed activity of the distal convoluted tubule

Mutations in the K+ channel KCNJ10 (Kir4.1) cause an autosomal recessive syndrome featuring seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME). Kir4.1 localizes to the basolateral membrane of the renal distal convoluted tubule, and its loss of function mimics renal features of Gitelman syndrome, with hypokalemic alkalosis, hypomagnesemia, and hypocalciuria. Presentation early in life due to seizures provides an opportunity to investigate the development of the electrolyte defect with age. We used DNA sequencing, electrophysiology, confocal imaging, and biochemistry to identify a new KCNJ10 mutation in a previously unreported family and determine its impact on channel function. We examined medical records to follow the development of electrolyte disorders with age. The four affected members were all homozygous for a novel T57I mutation that confers biochemical loss-of-function. Electrolytes in affected children were normal in the first years of life but showed significant worsening with age, resulting in clinically significant defects at age 5-8 years. Similar findings were seen in other SeSAME patients. These findings provide evidence for a delayed activity of salt reabsorption by the distal convoluted tubule and suggest an explanation for the delayed clinical presentation of subjects with Gitelman syndrome.